“Scientists are developing a drug which relieves fatigue after strenuous exercise - and it could benefit heart failure patients as well”, reports BBC News. Recent research has suggested that muscle fatigue is caused by calcium leaking into muscle cells, activating an enzyme that breaks down proteins in muscle. The report adds that researchers have developed a drug that blocks these leaks in mice and reduces their muscle fatigue after strenuous exercise. They say the drug may help treat people with heart failure.

This story is based on a laboratory study mainly in mice, looking at the effects of strenuous exercise on a particular group of proteins found in muscle cells - the ryanodine receptor channel complex.

These experiments have shown that this complex undergoes changes during exercise that make them leaky and therefore contribute to muscle fatigue. The research has also shown that a drug that stops these changes occurring can improve exercise capacity in mice. However, it is too early to know whether this drug will have a role to play in treating heart failure, and it will need to undergo rigorous testing before it can be used in humans.

Where did the story come from?

Dr Andrew Marks and colleagues at Columbia University and Appalachian State University in the US, and Montpellier University in France, carried out the research. The study was funded by the Defense Advanced Research Projects Agency and the American Heart Association. Some of the authors of the paper are consultants to ARMGO Pharma Inc., a company developing drugs that target the ryanodine receptor to treat heart failure and improve exercise capacity.

The study was published in the peer-reviewed scientific journal: Proceedings of the National Academy of Sciences of the USA.

What kind of scientific study was this?

This laboratory study looked at what happens in muscle cells during muscle fatigue and investigated drugs that can block these effects thereby reducing muscle fatigue. The researchers were particularly interested in a group of proteins called the ryanodine receptor complex, which regulates the release of calcium into muscle cells during contraction.

The researchers first looked at what happened to the ryanodine receptor channel complex in mouse muscle tissue after a programme of strenuous exercise (swimming twice daily for three weeks). They also looked at the complex after the period of strenuous exercise ended. Muscle strength was assessed after the exercise programme and in the period after the programme ended.

The researchers also took small samples (biopsies) of thigh muscle from trained human athletes who did strenuous cycling for three hours on three consecutive days. Samples were taken before and after the exercise period and the researchers looked at the ryanodine receptor channel complex in these samples.

Next, the researchers looked at how much exercise mice genetically engineered to have “leaky” complexes could do, compared to normal mice.

Normal mice were then randomly selected to either receive a drug (S107) that stops the complex “leaking” calcium into the cell or were part of a control group that received an inactive solution that did not contain the drug. These treatments were delivered by pumps implanted into the muscles, and treatment started four days before the swimming programme began.

Each week the mice’s exercise capacity was tested using a treadmill. Muscle strength was also measured in eight mice, four from each group. Further experiments looked at the effects of the drug on the flow of calcium in the muscles in response to stimulation.

What were the results of the study?

When the strenuous exercise ended, the mice’s muscle strength was reduced but recovered gradually. The researchers found that, in mice, the ryanodine channels changed and became more “leaky” after two weeks of strenuous exercise. The ryanodine complexes only partly changed backto their inactive state three days after the exercise programme finished. Human muscle samples also showed that the complex underwent similar changes after strenuous exercise.

Mice that were genetically engineered to have “leaky” ryanodine receptor channel complexes could do less exercise than normal mice, and showed signs of muscle damage after strenuous exercise.

Initially, mice treated with a drug to block the complexes becoming “leaky” had a similar exercise capacity to the control mice, but after three weeks they ran for a significantly longer amount of time (13 minutes more). Muscle strength was greater in mice treated with the drug than in control mice. Further experiments on individual ryanodine channels from the mice showed that those treated with the drug were less likely to be “leaky” than control mice.

What interpretations did the researchers draw from these results?

The researchers concluded that the ryanodine receptor channel complex undergoes changes during strenuous exercise that make the channels leaky, and these changes contribute to muscles becoming fatigued. Blocking this process using a drug called S107 can increase exercise capacity.

What does the NHS Knowledge Service make of this study?

This was a complex study that sheds light on what happens at the cellular level in the muscles of mice and men during strenuous exercise. The drug used in this study was used only on mice undergoing strenuous exercise, and will need to undergo rigorous testing before it can be used in humans. It is also too early to know whether this drug can be used as a treatment for heart failure, and more studies in animal models of heart failure would be needed before it is tested in people.